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Specific epigenetic modificationsDNA methylation

Methylation of 5 group of cytosines within CpG dinucleotides

Post-translational histone modifications

Methylation, ubiquitination, phosphorylation, sumoylation, acetylation of residues in the

N-terminal tails of histones

Chromatin remodelling

ATP dependent chromatin remodelling complexes shift nucleosomes

Histone variants

Histones with varying stabilities or specialist domains that alter the function of the nucleosome

Noncoding RNAs

piRNAs and other siRNAs that can direct epigenetic machineryLong noncoding RNAs may direct epigenetic enzymes to sites in the genome

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Almost exclusively occurs at CpG dinucleotides in mammals

Symmetrical, so able to be maintained through cell division

Cytosine 5- methyl cytosine

DNA methylation

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meCGGCme

Symmetric DNA methylation at CpG

dinucleotide

DNA methylation how does it occur?

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DNA methylation is laid down by de novo methyltransferases, DNMT3a

and DNMT3b in mammals

meCGGCme

Symmetric DNA methylation at CpG

dinucleotide

DNA methylation how does it occur?

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DNA methylation is laid down by de novo methyltransferases, DNMT3a

and DNMT3b in mammals

meCGGCme

meCG

GCme

GC

CG

Hemi-methylated DNA

+Hemi-methylated DNA

Symmetric DNA methylation at CpG

dinucleotide

DNA methylation how does it occur?

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DNA methylation is laid down by de novo methyltransferases, DNMT3a

and DNMT3b in mammals

meCGGCme

meCG

GCme

GC

CG

Hemi-methylated DNA

+Hemi-methylated DNA

DNA methylation is maintained

by DNMT1

Hemi-methylated DNA is thesubstrate for DNMT1

DNA methylation a stable epigenetic mark

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CpGs clustered into CpG islands, often at promoters of genes(Promoters are at the start of genes, where transcription machinery binds)

CpG islands tend to be protected from methylation Methylation at CpG island silencing of gene expression

Small subset of CpG islands that are dynamically methylated between cell types,most retain unmethylated status

Mainly studied for the inactive X chromosome

DNA methylation at CpG islands

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X inactivation demonstrates mitotic heritabilityof DNA methylation

X inactivation is an epigenetic dosage compensation mechanism in mammals, sothat males and females have the same dose of genes on the X chromosome

Random X inactivation occurs at gastrulation in the embryo, then this epigeneticstate is mitotically inherited by all daughter cells

Female XX Male XY

Inactive X chromosome showsDNA methylation of CpG islands

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meCpG in a CpG island is associated with the formation of a repressivechromatin structure (1o mechanism)

meCpG can be bound by methylated CpG binding proteins e.g. MeCP1 & 2- MeCP proteins have a DNA binding domain and transcriptional repression domain- MeCP proteins can recruit other factors that condense the chromatin

How does DNA methylation lead to silencing?

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meCpG can prohibit transcription factor binding, and alter geneexpression (2o mechanism, probably for rare transcription factors,

when CpG-poor promoters)

How does DNA methylation lead to silencing?

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